Polyalkylcyanoacrylate nanoparticles have been studied as potential drug carriers for sustained release formulations, for drug targeting and for improving the bioavailability of peptides and proteins such as insulin, calcitonin and growth hormone releasing factor (Damge, C. et al., Diabetes, 37:246(51) (1988); Lowe, P. et al., J. Pharma. Pharmacol., 46:547-52 (1994); and Gautier, J. et al., J. Controlled Release, 20:67-78 (1992)). The short chain cyanoacrylate monomers, such as n-butyl, isobutyl and isohexylcyanoacrylate, are typically used because of their short degradation times and low toxicities.
Two methods are commonly employed for the preparation of these nanoparticles: the interfacial polymerisation method and the anionic polymerisation method. In the interfacial polymerisation method, the monomer and the drug are dissolved in an organic phase with polymerisation occurring at the organic-aqueous interface upon addition of the organic phase to an aqueous phase (Al Khouri, N. et al., Int. J. Pharm., 28:125-32 (1986). This method produces nanocapsules. In general, prior art peptide loaded nanoparticles have been produced by this technique (see, e.g., EP-A-0 608 207; EP-A-0 447 318; and FR-A-2,515,960).
Anionic polymerisation occurs in aqueous media at low pH and is catalyzed by hydroxyl ions. In this method, the drug can be incorporated within the nanoparticle, adsorbed onto the nanoparticles or a combination of both depending on the time of addition of the drug to the polymerisation medium (Couvreur, P. et al., J. Pharma. Pharmacol., 31:331-2 (1979)).
Vidarabine-associated polyalkylcyanoacrylate nanoparticles, which result from vidarabine chemically interacting with the cyanoacrylic monomer during the polymerisation process, have been made using the anionic polymerisation method modified by the mandatory inclusion of dioctylsulfosuccinate in the aqueous media. However, formation of the polyalkylcyanoacrylate/vidarabine complex inactivated the biological activity of the vidarabine (Guise, V., et al., Pharmaceutical Res., 7:736-41 (1990)).
Administration of exogenous insulin can ameliorate metabolic abnormalities in type II diabetes by compensating for reduced endogenous insulin secretion, reducing excessive hepatic glucose production and stimulating glucose uptake. Additionally, non-substitutional insulin administration in non-insulin dependent diabetes is indicated where, without it, satisfactory compensation of diabetes is not achieved. Side effects possible from insulin therapy include weight gain, hyperinsulinemia and hypoglycemia.
Although single or multiple daily subcutaneous injections of insulin are the mainstay of insulin delivery techniques, several other methods of insulin delivery are now available or in development, including (a) continuous subcutaneous insulin infusion by a wearable infusion pump; (b) total or segmental transplantation of a pancreas; (c) transplantation of isolated islet cells; (d) implantation of a programmable insulin pump; (e) oral, nasal, rectal and transdermal mechanisms of insulin delivery; (f) administration of insulin analogues; (g) implantation of polymeric capsules which give continuous or time-pulsed release of insulin; and (h) implantation of a biohybrid artificial pancreas which uses encapsulated islets. Despite these advances, the ideal delivery of insulin to patients has yet to be developed. For instance, subcutaneous and oral methods of insulin delivery do not currently mimic physiological insulin needs and transplantation requires risky immunosuppression.
Thus, there exists a need for improved insulin formulations, particularly controlled release bioactive oral formulations including those targeted to the small intestine and controlled release parenteral formulations to mimic physiological insulin needs.